Homozygous familial hypercholesterolaemia (HoFH): causes, diagnosis and treatment

Familial hypercholesterolaemia (FH) is a genetic condition that raises blood cholesterol to very high levels from birth because the liver cannot clear cholesterol properly. The British Heart Foundation says it affects about 1 in every 250 people. HEART UK explains that HoFH is the more severe form and that it is very rare, with an estimated one in 250,000 people affected.

The difference is genetic. Everyone has two copies of each gene, one from each parent. In FH there is one altered copy, and in HoFH there are two, one from each parent. HEART UK says HoFH is so rare because you can only inherit it if both parents have FH. The altered genes usually affect the LDL receptors, little structures that catch LDL cholesterol (often called bad cholesterol) in the blood and take it into cells.

HEART UK describes three genes involved in FH and HoFH. Changes in the LDL receptor gene mean there are not enough LDL receptors, and this is the most common. A change in the APOB gene means the receptors cannot bind well to cholesterol, which is unusual. A change in the PCSK9 gene means receptors are broken down in the liver.

It also describes two main types. Most people with HoFH are receptor defective, meaning up to a quarter of their LDL receptors work. Others are receptor negative, with fewer than 2% working. The type affects which treatments are suitable. If the two altered genes are identical it is homozygous FH, and if they are different it is compound heterozygous FH, which may also be called HoFH because the effect on the body is similar.

For two people who both have FH, HEART UK says that on average out of four children, two would inherit FH, one would inherit HoFH and one would inherit neither altered gene. These are chances for each pregnancy, not a prediction for a family.

When LDL cholesterol is too high, HEART UK explains, it is laid down in blood vessel walls, which narrow and make it harder for blood to flow. This is atherosclerosis. Blood clots can also form, causing heart attack or stroke. It is a process that normally happens gradually with age, but with HoFH it begins from childhood and is caused by genes.

HEART UK lists physical signs that can appear in childhood: fatty lumps under the skin (cutaneous xanthoma) or on tendons of the knuckles and ankles (tendon xanthoma) before the age of 10, a white arc or ring around the edge of the iris (corneal arcus) before the age of 10, and evidence of aortic valve disease before the age of five.

HEART UK says HoFH is diagnosed by combining cholesterol testing, checking for physical signs, questions about family and personal history of heart disease, and genetic testing. As a guide, LDL cholesterol is usually above 11 mmol/L in children under 18 and above 13 mmol/L in adults. NICE guidance for FH says clinicians should consider a clinical diagnosis of HoFH at those levels, and that children at risk because two parents are affected should have their LDL measured before the age of 5 or at the earliest opportunity.

Sometimes cholesterol is not as high as expected, so clinicians can consider tests for early heart disease, family history and genetic testing. Genetic testing can confirm the diagnosis and identify exactly which genes are involved, which helps target treatment. If you have FH and have children, HEART UK advises getting them tested as early as possible so treatment can start in childhood.

NICE says people with a clinical diagnosis of HoFH should be referred to a specialist centre and, on diagnosis, offered referral for evaluation of coronary heart disease.

HEART UK says people with HoFH are treated by specialists in a lipid clinic, who work with them to find the right combination of treatments. The following are described.

NICE guidance on familial hypercholesterolaemia says healthcare professionals should consider offering LDL apheresis for adults and children and young people with HoFH, and that in children and young people lipid-modifying drug therapy should be considered before LDL apheresis. It says liver transplantation should be considered as an option after drug therapy and apheresis.

It also says that shared care between cardiology and obstetrics should be arranged for women with FH who are considering pregnancy or are pregnant, including assessment of coronary heart disease risk, particularly to exclude aortic stenosis, and that this is essential for women with HoFH. People with FH who do not smoke, especially children, should be strongly discouraged from starting.

HEART UK says a healthy lifestyle will not be enough on its own for HoFH but helps keep cholesterol down alongside treatment: avoiding alcohol and smoking, being a healthy weight, being active and eating healthily. If you take lomitapide, you will need a low-fat diet with less than 20% of energy from fat, avoidance of grapefruit and Seville oranges, and supplements, and you will be offered a dietitian.

Living with a rare, invisible condition that needs frequent treatment can be demanding. Support from the lipid clinic, patient organisations such as HEART UK, and family members who are also affected can help. If you have chest pain, breathlessness, or symptoms that could suggest a heart problem, call NHS 111, or 999 in an emergency, and tell clinicians you have HoFH.

HoFH treatment, including apheresis and specialist medicines, is delivered through NHS lipid clinics and specialist centres. HEART UK notes lomitapide is available on the NHS in England. Because the condition is so rare, a private opinion is usually from the same small pool of specialists, so many people stay within the NHS lipid service and use second opinions only to confirm plans. Make sure your GP holds a copy of your diagnosis and treatment plan.